When someone starts immunotherapy, the first thing they usually ask me is what to add. A mushroom extract, a high-dose supplement, a new diet, mistletoe (which does have a real place alongside immunotherapy, bonus paragraph on this at the end). We are all chasing thing that will make the drug work better and your response more robust.
My first two answers tend to surprise people. One is about the clock. The other is about the gut. Both come from the same idea: immunotherapy works only as well as the immune system it works through.
Why your immune system matters more here
Checkpoint inhibitors such as pembrolizumab, nivolumab, and atezolizumab do not directly attack the tumor. Instead, they release a brake on your T cells, allowing an immune response that may already be present to do its job. This is fundamentally different from chemotherapy, which kills rapidly dividing cells whether or not the immune system is engaged. Immunotherapy, by contrast, depends on the immune system recognizing and responding to the tumor.
So two ordinary things start to matter: what time of day your immune system meets the drug, and which bacteria in your gut are training it.
Change one: Ask for a morning infusion
Your immune system runs on a daily rhythm. T cells move in and out of your lymph nodes on a schedule, and so do the cells that show them what to attack. We have seen this play out with vaccines for years. In older adults, flu shots given in the morning produce a stronger antibody response than the same shot given late in the afternoon.
It made sense to ask whether immunotherapy works the same way, and the early answers were loud. A melanoma study out of Emory found that patients who got more of their infusions late in the day did much worse. I'll admit I read anything from Emory a little more closely; it's my son's name.
Dozens of similar studies followed in lung, kidney and other cancers, and a systematic review this spring estimated that earlier infusions cut the risk of death by about 40%. That is roughly the same magnitude of benefit these drugs showed over chemotherapy in the trials that led to their approval. Taken at face value, moving an infusion a few hours earlier would be doing as much good as the drug itself.
Here’s the problem with those studies. Almost all of these studies looked back at appointment records, and the last slot of the day tends to collect the sickest patients: the ones whose labs had to be repeated or whose clinic visit ran long. Patients who do well also stay on treatment for years and collect a mix of times, while patients who progress quickly get only a few infusions, so one or two late ones look like a pattern.
This month, a commentary in Cancer Cell from Christoph Scheiermann's lab, one of the main groups studying the immune system's daily clock, reviewed the evidence. Their summary: timing can change how well these drugs work in animals, and several studies of patient records point the same way, but it is still unclear whether those patient results will hold up, why exactly they happen, and whether they should change how we treat people. Cancer Ecology by Ken Pienta flagged it last week in a piece worth reading, and I recommend his Substack often. His point is that we specify the dose and order of every cancer drug, yet rarely record the hour it was actually given. That detail may matter more than we have assumed, and we can't evaluate it if nobody writes it down.
The most impressive and the only randomized trial - a lung cancer study that reported infusions before 3 p.m. nearly doubled the time before the cancer grew - was retracted in June after the journal found serious problems with how the trial was registered and run and with the data itself. Bummer.
What is left are two large, careful studies that point in different directions. A Veterans Affairs study drawing on nearly 5,000 lung cancer patients found that patients whose first immunotherapy infusions were given before noon lived about two months longer. The researchers also checked veterans getting chemotherapy alone, which does not rely on the immune system the way checkpoint drugs do, and found no survival difference by time of day. On the other side, a pooled look at more than 3,000 patients from eight lung cancer trials, presented this spring, found no survival difference between morning and afternoon. My guess is that trial patients tend to be healthier and more closely managed than patients in everyday care. All eight trials also used a single drug, atezolizumab, which blocks PD-L1, while most lung cancer patients outside trials get a PD-1 drug such as pembrolizumab. In several of the trials, atezolizumab was given alongside chemotherapy, which may have blurred any timing effect. And the result itself cannot rule out a small benefit about the size the VA study found.
What I tell patients. The effect of a morning infusion is probably modest, but it is free, carries no risk, and the biology behind it is sound, so I still ask every patient to try for it. Ask for an appointment before noon if your center can do it, and ask at scheduling for it as a standing preference for the whole course rather than one visit at a time. Then let it go. Do not delay a cycle or turn down an afternoon slot today for a morning one three weeks out. Getting treatment on time matters more than the hour. If you get chemotherapy the same day, the morning slot matters for the immunotherapy, since chemotherapy runs on a different clock. I went deeper on circadian rhythm in cancer care, including light, meal timing, sleep and chemotherapy timing, in a talk I gave to naturopathic physicians this spring. It's technical, but it's open to anyone.
Change two: the right bacteria, and the food they live on
The bacteria in your gut shape how your immune system responds to these drugs. When researchers transferred stool from patients who responded to immunotherapy into mice, the mice responded too. Mice given stool from patients who had not responded did not respond either. This was tried in humans too. In small trials, stool transplants helped some melanoma patients whose cancer had stopped responding start responding again, and in a placebo-controlled trial, kidney cancer patients who received real donor stool went longer before their cancer grew, though the trial narrowly missed its main goal. Fecal transplants are mostly only available through clinical trials, and one donor was linked to serious immune side effects, so ask your doc rather than trying anything DIY at home.
The researchers behind the mouse work also found that antibiotics around the start of treatment were linked to worse outcomes in patients.
One bacterium keeps showing up in these studies: Akkermansia muciniphila. It lives in the mucus layer that lines your gut and helps keep that barrier intact. In a large French-led study of lung cancer patients, those who had Akkermansia in their stool before starting immunotherapy responded better and lived longer. The same study found that very high levels, often after a course of antibiotics, went along with a worse response. The goal is a healthy amount of Akkermansia inside a diverse gut, not a gut flooded with one species.
Early trials giving Akkermansia alongside immunotherapy have been safe so far. Though sometimes simply supplementing Akkermansia does not work. It feeds on the gut's own mucus rather than fiber, so fiber matters in a different way: it keeps that mucus layer healthy, and on a low-fiber diet Akkermansia can start wearing down the barrier it normally protects. Polyphenol-rich foods such as cranberries, grapes and pomegranate seem to raise it more reliably than fiber supplements like inulin.
The second strain I use is Clostridium butyricum MIYAIRI 588, usually called CBM588. It produces butyrate, a fatty acid that feeds the gut lining and helps tune T cells, and it is one of the most commonly prescribed probiotics in Japan. In two small randomized trials in kidney cancer, adding CBM588 to nivolumab and ipilimumab or to cabozantinib and nivolumab led to higher response rates. Lung cancer patients in Japan who took it also lived longer on immunotherapy, including those who had needed antibiotics. The kidney trials had about 30 patients each… promising rather than settled.
The strain matters. In a study of melanoma patients at MD Anderson, those taking an ordinary store-bought probiotic tended to do worse on immunotherapy, and in mice, a generic probiotic blunted the drug’s effect. The patients who did best ate plenty of fiber and took no probiotic at all.
Feeding the good guys. The butyrate producers feed on fiber, and Akkermansia does best in a gut with a well-fed mucus layer and plenty of plant compounds, so the supplement helps most if you keep feeding what it seeds. Camu camu, a polyphenol-rich Amazonian berry, is one of the few prebiotics tested alongside immunotherapy in people. In a small randomized trial in kidney cancer, adding it to nivolumab and ipilimumab delayed progression, but patients taking it had an unusual pattern of immune side effects, including six cases of adrenal insufficiency. That fits what we know: nivolumab plus ipilimumab already causes more immune side effects than any other checkpoint combination, adrenal and pituitary problems among them, and anything that ramps the immune system up further could plausibly add to that. So I only use it with close monitoring.
What about skipping the bacteria and taking butyrate itself? I would hold off. I could not find a single study testing a butyrate supplement alongside immunotherapy in people. Butyrate made by your own gut bacteria in the colon is linked to better results on PD-1 drugs, but butyrate in the bloodstream is a different story. In people on ipilimumab, high blood butyrate went with a worse response, and in mice it held back the very immune cells the drug is trying to switch on. Butyrate calms the immune system, which is helpful for an inflamed gut and the opposite of what immunotherapy needs. Oral butyrate supplementation is also likely to raise blood levels more than colon levels. CBM588 makes butyrate in the colon, which is different from raising blood levels. So I let the bacteria and the fiber make butyrate in the colon, where it seems to help.
What I tell patients. Take Akkermansia and/or CBM588 during immunotherapy, and stop any general probiotic blend you are already taking. Each has been studied separately, not together, so combining them is my clinical judgment rather than a tested pairing. Eat a wide range of plants every day: beans, lentils, oats, vegetables, berries, nuts and seeds. Question every antibiotic, and take the ones you actually need. Tell your oncology team what and how much you are taking.
For Akkermansia, I use Pendulum Akkermansia. I picked it for three reasons. It contains live bacteria, which is the form used in the immunotherapy research. It is a single strain, so you are adding Akkermansia and nothing else. And it comes with a small amount of chicory inulin, a fiber that feeds the bacteria around it. No Akkermansia product on the market has been tested alongside immunotherapy yet, so this is the closest match to the research rather than a proven pairing. Some products, such as Pendulum's Metabolic Daily, bundle Akkermansia with a different Clostridium butyricum strain. The immunotherapy data is for CBM588 specifically, and I am not aware of any product that combines it with Akkermansia.
CBM588 is somewhat hard to find the in US. The easiest source i’ve found is Strong Miyarisan, the Japanese over-the-counter version made by Miyarisan, the company behind CBM588. Upolife ships it from a US warehouse in 2 to 4 business days, about $33 for 330 tablets. The label names the Miyairi strain without the 588 number, but it comes from the same maker as Miya-BM, the prescription version used in the Japanese lung cancer studies. The adult label dose is 3 tablets three times a day after meals, and it contains lactose. If you want the strain named on the box, Butirrisan, an Italian CBM588 product, ships from Italy in 10 to 15 business days for about $129 plus a 15% import duty, and supplements cannot be returned. In Europe the same strain is also sold as Therascience Teoliance CBM588, about €41 for 90 tablets. Other Clostridium butyricum strains are also sold in the US: AOR Probiotic 3, on my Fullscript, uses strain TO-A, and Pendulum's blends use WB-STR-0006. Neither strain has been studied alongside immunotherapy.
Bonus: mistletoe
Mistletoe is the question I get most after these two. In German lung cancer registries, patients who added it to their checkpoint inhibitor lived noticeably longer, and a follow-up look at more than 400 patients found people on the combination were no more likely to stop treatment because of side effects. That matches the first small safety study of the combination. These studies looked back at records rather than randomizing anyone, and the largest placebo-controlled trial, in advanced pancreatic cancer without immunotherapy, found no benefit. Prospective trials are finally underway: one in Switzerland is adding mistletoe to checkpoint inhibitors across several solid tumors, and a second is pairing it with pembrolizumab in triple-negative breast cancer. I use it with many of my immunotherapy patients, and I’m glad to see it finally being tested properly alongside these drugs.
Ksenia Malarkey, ND is a naturopathic physician specializing in integrative oncology, hormones, and metabolic health.
She provides medical care for Washington and Oregon residents and offers global health coaching.
To schedule a free 15-minute consult, visit drkseniamalarkey.com
Products I recommend are available through my Fullscript dispensary.